Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

Sanz, Pascual; Serratosa, José M.; Sánchez, Marina P.

doi:10.3390/ijms22105351

Cited by 21 publications

(32 citation statements)

References 128 publications

(199 reference statements)

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“…However, treatment with AMPK activators could attenuate these behavioral and molecular changes in the pathophysiological profile of metabolic dysfunction (Wang et al 2018 ). Various studies have shown that treatment with metformin is effective in neurological diseases, including high MPTP and increased BDNF (Patil et al 2014 , Lu et al 2016 ), Parkinson’s disease (Choi et al 2010 ; Arbeláez-Quintero and Palacios 2017 ; Lu et al 2020 , Paudel et al 2020 ), epilepsy (H S, Paudel et al 2019 , Demaré et al 2021 ; Sanz et al 2021 , Salvati et al 2022 ), traumatic brain injury (Tao et al 2018 ; Taheri et al 2019 ; Fan et al 2020 ; Rahimi et al 2020 ), neuroprotection of the heart (Zhu et al 2018 , Benjanuwattra et al 2020 , Leech et al 2020 ), and preconditioning in ischemic brain injury (Wang et al 2021a , b , c ). Various studies have shown that BDNF can affect the structure of the anal sphincter (Singh and Rattan 2021 , Singh, Singh et al 2021 ).…”

Section: Metformin and Therapeutic Goalsmentioning

confidence: 99%

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

Hasanvand

2022

Inflammopharmacol

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Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner (SHP) expression in the liver cells. The main mechanism of metformin’s action is related to its activation of the AMPK enzyme and regulation of the energy balance. AMPK is a heterothermic serine/threonine kinase made of a catalytic alpha subunit and two subunits of beta and a gamma regulator. This enzyme can measure the intracellular ratio of AMP/ATP. If this ratio is high, the amino acid threonine 172 available in its alpha chain would be activated by the phosphorylated liver kinase B1 (LKB1), leading to AMPK activation. Several studies have indicated that apart from its significant role in the reduction of blood glucose level, metformin activates the AMPK enzyme that in turn has various efficient impacts on the regulation of various processes, including controlling inflammatory conditions, altering the differentiation pathway of immune and non-immune cell pathways, and the amelioration of various cancers, liver diseases, inflammatory bowel disease (IBD), kidney diseases, neurological disorders, etc. Metformin’s activation of AMPK enables it to control inflammatory conditions, improve oxidative status, regulate the differentiation pathways of various cells, change the pathological process in various diseases, and finally have positive therapeutic effects on them. Due to the activation of AMPK and its role in regulating several subcellular signalling pathways, metformin can be effective in altering the cells’ proliferation and differentiation pathways and eventually in the prevention and treatment of certain diseases. Graphical abstract

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Section: Metformin and Therapeutic Goalsmentioning

confidence: 99%

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

Hasanvand

2022

Inflammopharmacol

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“…Metformin has been observed to regulate oxidative balance in various studies by inhibiting the complex I enzyme in the electron transport chain (ETC) ( Fontaine, 2018 ; Vial et al, 2019 ; Wang et al, 2019 ). Reactive oxygen species (ROS) production is directly restricted by inhibiting mitochondrial complex I and modulating the respiratory chain ( Sanz et al, 2021 ). Upon metformin administration, ROS production is reduced and an enhanced anti-oxidant system is witnessed ( Ouslimani et al, 2005 ; Diniz et al, 2016 ).…”

Section: Biological Activities Of Metforminmentioning

confidence: 99%

“…Upon metformin administration, ROS production is reduced and an enhanced anti-oxidant system is witnessed ( Ouslimani et al, 2005 ; Diniz et al, 2016 ). In animals, metformin is reported to increase levels of endogenous proteins such as thioredoxin (Trx), sirtuin 3, and glutathione to counteract the attack of free radicals produced during variety of disorders, including age-related neurodegeneration, epilepsy ( Sanz et al, 2021 ), cardiovascular disease, cancer, inflammation, and osteoporosis. The AMPK pathway increases the expression of Trx, an oxidoreductase enzyme.…”

Section: Biological Activities Of Metforminmentioning

confidence: 99%

“…Also, the activated AMPK pathway regulates GLUT1 translocation to the plasma membrane, enhancing glucose uptake and glycolysis and preserving neuronal-metabolic functionality ( Sanz et al, 2021 ). In Alzheimer’s and Parkinson’s diseases, alpha-synuclein protein (SNCA) accumulates within the Lewy bodies of neural tissues.…”

Section: Biological Activities Of Metforminmentioning

confidence: 99%

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Metformin: Activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action

Goel

Singh²,

Singh³

et al. 2022

Front. Genet.

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Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body’s response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5′ AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review’s objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin’s efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.

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“…Diabetes has been linked to an increased risk of epileptic seizures in epidemiologic studies [6][7][8][9] . Some antiglycemic drugs, such as liraglutide, sitagliptin, rosiglitazone, and metformin, have been shown in animal studies to be effective in reducing seizures and improving cognitive impairment [10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Genetic Prediction of Antiglycemic Drug Targets and Risk of Epilepsy: A Mendelian Randomization Study

Zhou

Yang

et al. 2023

Preprint

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Diabetes has been linked to an increased risk of epilepsy in observational studies. The antiglycemic drugs have been shown in animal studies to improve seizures. However, whether the associations between antiglycemic drugs and epilepsy in human is not known. In this study, we conducted a Mendelian randomization investigation to assess the potential causal role of antiglycemic drug targets in epilepsy.We used the International League Against Epilepsy Data as the discovery set and FinnGen Data as the replication set .Three antidiabetic drug target genes, including ETFDH, CYP21A2, and CYP2D6 were discovered to be involved in epilepsy. ETFDH predicted as a target gene in the discovery set (IVW, OR = 1.018, 95% CI, 1.004–1.033, p = 0.009), replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016) and CYP21A2 gene in the discovery set (IVW, OR = 1.029, 95% CI, 1.005– 1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) showed a causal association with an increased risk of epilepsy. In contrast, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and the replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). By searching the pharmacological effects of anti-glucose drug target gene related drugs and binding drugs in DrguBank, Metformin was found to be ETFDH gene inhibitor, showing a potential therapeutic effect on epilepsy.

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Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

Cited by 21 publications

References 128 publications

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

Metformin: Activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action

Genetic Prediction of Antiglycemic Drug Targets and Risk of Epilepsy: A Mendelian Randomization Study

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